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Molecular Oncology, Markers, Clinical Correlates |
Parker Hughes Cancer Center and Children’s Cancer Group ALL Biology Reference Laboratory, Hughes Institute, St. Paul, Minnesota 55113 [L. S., M-L. C., C. N., A. V., C. M., F. M. U.]; Group Operations Center, Children’s Cancer Group, Arcadia, California 91066 [H. S., M. S.]; Department of Pediatrics, University of Chicago, Chicago, Illinois 60601 [J. N.]; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [P. G. S.]; Department of Hematology-Oncology, Children’s Hospital Los Angeles, Los Angeles, California 90027 [P. S. G.]; and Children’s National Medical Center and the George Washington University, Washington, D.C. 20010 [N. S., G. H. R.]
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ABSTRACT |
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KSSMPQKFLG) upstream to the transcription activation domain and adjacent to the COOH-terminal zinc fingers of Ik-2, Ik-4, Ik-7, and Ik-8. Thus, children with T-ALL express high levels of dysfunctional dominant-negative Ikaros isoforms. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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50,000/µl), nonwhite race, age 10 years, marked enlargement of the spleen, liver, and lymph nodes, and bulky disease of the mediastinum. Children with T-ALL have a poor prognosis unless they are treated with very intensive chemotherapy regimens (3)
. A better understanding of the biological basis of T-ALL should lead to the development of innovative and more effective treatment programs for patients with this distinct form of leukemia. Ikaros, a member of the Kruppel family "zinc finger" DNA-binding proteins, is one of the critical transcriptional regulators of lymphocyte ontogeny and differentiation in amphibian, teleost, avian, and murine species (4, 5, 6, 7, 8, 9, 10) . Alternatively spliced transcripts of the Ikaros gene encode at least eight zinc finger proteins with distinct DNA-binding capabilities and specificities (Ikaros isoforms Ik-1 through Ik-8; Refs. 4 and 5 ). Ikaros proteins are highly conserved between human and mouse, and all share a common COOH-terminal domain containing a bipartite transcription activation motif and two zinc finger motifs required for hetero- and homodimerization among the Ikaros isoforms and interactions with other proteins (4 , 7) . They differ in their NH2 -terminal zinc finger (F1 through F4) composition and in their overall DNA binding and transcriptional activation properties. At least three NH2 -terminal zinc fingers are required for high-affinity DNA binding to the 4-bp core motif GGGA. Thus, only the isoforms Ik-1, Ik-2, and Ik-3, which contain at least three NH2 -terminal zinc fingers, exhibit high-affinity DNA binding. These DNA-binding isoforms localize to the nucleus, whereas isoforms Ik-4 through Ik-8, which have fewer than three NH2 -terminal zinc fingers, localize to the cytoplasm (4 , 7) . The formation of homo- and heterodimers among the DNA-binding isoforms increases their affinity for DNA, whereas heterodimers between these DNA-binding isoforms and those without an intact DNA-binding domain are unable to bind DNA and are therefore transcriptionally inactive (7) . Therefore, Ikaros proteins with fewer than three NH2 -terminal zinc fingers can exert a dominant-negative effect by interfering with the activity of Ikaros isoforms that can bind DNA (7) .
Homozygous deletion of the Ikaros exons 3 and 4 encoding three NH2 -terminal zinc fingers required for sequence-specific DNA binding of Ikaros results in a complete arrest in the development of all lymphoid lineages in mice (4) . Mice heterozygous for this mutation express higher than normal levels of Ik-6, Ik-7, and Ik-8 isoforms and develop a highly aggressive form of T-cell leukemia with a concomitant loss of heterozygosity between 3 and 6 months after birth (4 , 6) . Immediately prior to development of leukemia, lymphocyte precursors show a significant decrease in their Ikaros-specific DNA-binding activity, along with a change in compartmentalization of Ikaros from nucleus to cytoplasm (7) .
On the basis of the critical role played by Ikaros in the development of the normal immune system in mice and the rapid development of T-cell leukemia in germ-line mutant mice expressing dominant-negative isoforms of Ikaros, we sought to determine whether specific molecular defects involving this candidate leukemia suppressor gene may contribute to the leukemogenesis of T-ALL in children. Using multiple molecular, biochemical, and immunological techniques to examine Ikaros gene expression and function, we have demonstrated that primary leukemic cells from children with T-ALL express high levels of dysfunctional dominant-negative Ikaros isoforms. These findings support the hypothesis that the expression of dominant-negative Ikaros isoforms and the disruption of normal Ikaros function may contribute to the development of childhood T-ALL. These results are consistent with and extend our recent study that implicated dominant-negative isoforms of Ikaros in the leukemogenesis of infant ALL (8) .
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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50,000/µl or age 10 years) and CCG 1901 (for ALL patients with lymphomatous features, including T-ALL). Three patients with T-ALL in first bone marrow relapse also were studied. Each protocol was approved by the National Cancer Institute as well as the Institutional Review Boards of the participating CCG-affiliated institutions. Informed consent was obtained from parents, patients, or both, as deemed appropriate, for both treatment and laboratory studies, according to Department of Health and Human Services guidelines. Diagnosis of ALL was based on morphological, biochemical, and immunological features of the leukemic cells, including lymphoblast morphology as determined by Wright-Giemsa staining, positive nuclear staining for terminal deoxynucleotidyl transferase, negative staining for myeloperoxidase, and reactivity with monoclonal antibodies to lymphoid differentiation antigens, as described previously (11
, 12)
. All 18 patients of the present study were classified as T-ALL because 30% of the isolated leukemic cells were positive for the pan-T cell marker CD7 (range, 47–99%, median, 90%), and <30% were positive for the pan-B cell marker CD19 (Table 1)
. Surplus cells from diagnostic bone marrow specimens were used for molecular genetic studies. Among the 15 newly diagnosed patients, 6 (40%) were 10 years of age, 9 (60%) were male, 14 (96.6%) had high WBC counts (range, 71,000/µl-819,000/µl; median, 500,000/µl), 12 (80%) had hepatosplenomegaly, and 11 (73.3%) had a mediastinal mass (Table 1)
. All 15 newly diagnosed patients had high-risk ALL according to the National Cancer Institute risk classification. These presenting features are typical of children with T-ALL (3
, 11
, 12)
.
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RT-PCR and Nucleotide Sequencing.
All RT-PCR assays for Ikaros mRNA expression were performed centrally in the CCG ALL Biology Reference Laboratory, with all due precautions to avoid false positive results, as described previously in detail (8)
. For enhanced sensitivity, the PCR products were amplified further by nested PCR. Primers for Ikaros cDNA amplification were: F1, 5'-ATGGATGCTGACGAGGGTCAAGAC-3'; and R1, 5'-TT-AGCTCATGTGGAAGCGGTGCTC-3'. Primers for nested PCR were: F2, 5'-CTCATCAGGGAAGGAAAGCC-3'; and R2, 5'-GGTGTACATGACGTGATCCAGG-3'. Reactions conducted with RNA isolated from normal fetal thymocytes/infant bone marrow mononuclear cells were used as positive controls for Ikaros transcripts. Negative controls included PCR products from an RNA-free cDNA synthesis and amplification reaction and a DNA polymerase-free reaction.
Purified RT-PCR products (QIAquick PCR purification kit; Qiagen, Santa Clarita, CA) were cloned into the pCR II vector using the TA Cloning kit (Invitrogen, San Diego, CA). The cloned PCR products were purified with a Qiagen plasmid isolation kit and sequenced automatically with the Thermosequenase sequencing kit (Amersham, Arlington Heights, IL) and the ALF Sequencer (Pharmacia, LKB Biotech, Piscataway, NJ). The sequences were compared with the published human Ikaros cDNA sequence obtained through GenBank (accession codes Sarcoma 180876 and U40462).
The predicted amino acid sequence of an insertion due to a 60-bp insertion found in Ikaros 2 coding sequence from PCR clones of some leukemic T-cells was analyzed using a homology model based upon the crystal structure of the zinc finger transcription factor Zif268/EGR-1 to predict its impact on the protein structure and function of Ikaros 2 (13
, 14)
. Zif268 has three zinc fingers with a primary sequence motif, which is similar to that of Ik-2 (13)
. The length and finger connection of the last two zinc fingers in Zif268 are identical to those of the first three Ik-2 zinc fingers, except the third Ik-2 zinc finger is only one amino acid longer. Therefore, we used the crystal structure of Zif268 as a structural template in modeling the Ik-2 DNA binding domain. The Ik-2 amino acid sequence was first aligned with the Zif268 sequence. On the basis of the sequence alignment, the coordinates of the Ik-2 zinc fingers were assigned automatically using the homology module of INSIGHTII (Molecular Simulation, Inc., San Diego, CA). The model was then extended to include the exon 2a sequence based on the secondary structure prediction using the LASERGENE program (DNASTAR, Inc., Madison, WI), and the C
positions of the region were assigned manually using "O" program (14)
. Finally, the ribbon representation of the model including the three zinc fingers and a DNA duplex were done based on the homology model.
Western Blot Analysis of Ikaros Protein Expression.
Whole-cell lysates were prepared using a 1% NP40 lysis buffer, as described (8)
. Western blot analysis of whole-cell lysates for Ikaros expression was performed by immunoblotting using a polyclonal anti-Ikaros antibody reactive with all eight Ikaros isoforms and the enhanced chemiluminescence (ECL) detection system (Amersham Life Sciences), as described previously (8)
.
Subcellular Localization Studies Using Confocal Laser Scanning Microscopy.
The subcellular localization of Ikaros protein(s) was examined by immunofluorescence and confocal laser scanning microscopy, as described (8)
. To detect the Ikaros protein, cells were incubated with an affinity-purified polyclonal rabbit anti-Ikaros antibody of 1:300 dilution for 1 h at room temperature. Cells were washed with PBS and incubated with a FITC-conjugated goat anti-rabbit IgG (Amersham Corp., Arlington Heights, IL) at a 1:40 final dilution for 1 h. Cells were washed with PBS, counterstained with the DNA-specific nuclear dye toto-3 (Molecular Probes, Inc.) at a 1:1000 dilution for 10 min at room temperature, and washed again with PBS. The coverslips were inverted, mounted onto slides in Vectashield (Vector Labs, Burlingame, CA) to prevent photobleaching, and sealed with nail varnish. Slides were examined using a Bio-Rad MRC 1024 Laser Scanning Confocal Microscope mounted on an Nikon Eclipse E-800 upright microscope equipped for epifluorescence with high numerical aperture objectives. Optical sections were obtained and turned into stereomicrographs using Lasersharp software (Bio-Rad, Hercules, CA). Representative digital images were processed using the Photoshop software (Adobe Systems, Mountain View, CA). Images were printed with a Fuji Pictography thermal transfer printer (Fuji Photo, Elmsford, NY).
EMSA.
Nuclear extracts were prepared by the method of Dignam et al. (15)
. The Ik-BS1 (5'-TCAGCTTTTGGGAATACCCTGTCA-3') oligonucleotide probe containing a high-affinity Ikaros binding site was end-labeled with [
-32 P]ATP (3000 Ci/mmol) using T4 polynucleotide kinase and purified using a Nuctrap probe purification column (Stratagene). Three-µg samples of the nuclear extracts and 1 ng of labeled Ik-BS1 probe (1 x 105 cpm/ng) were used in the DNA binding reaction. For competition reactions, 60-fold excess unlabeled specific or nonspecific oligonucleotides were added prior to the addition of the labeled Ik-BS1 probe. The Ik-BS1 oligonucleotide was used as the specific competitor, and the Ik-BS1M oligonucleotide (5'-TCAGCTTTTGGGggTACCCTGTCA-3'), which contains a 2-bp mutation at the Ikaros binding site, was used as the nonspecific competitor.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Fig. 1A
). In contrast, MOLT-3 cells, JK-E6–1 cells, and primary leukemic cells from all T-ALL patients primarily expressed smaller immunoreactive proteins of Mr 
37,000–40,000, corresponding in size and electrophoretic mobility to the dominant-negative Ikaros isoforms Ik-4, Ik-5, Ik-6, Ik-7, and Ik-8 lacking critical NH2 -terminal zinc fingers involved in DNA binding (Table 2
; Fig. 1, B–D
).
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; Fig. 2A
). These findings are consistent with previous reports regarding the exclusively nuclear localization of Ikaros proteins in normal mouse thymocytes and in transfected fibroblast cells ectopically expressing the DNA-binding Ikaros isoforms Ik1, Ik2, or Ik3 (4
, 7)
. In contrast, Ikaros proteins were expressed predominantly in the cytoplasm of leukemic T-cells from 7 of 11 children (64%) with T-ALL as well as JK-E6–1 and MOLT-3 leukemic T-cell lines, as evidenced by a bright green fluorescent rim surrounding the toto-3-labeled blue nuclei (Table 2
; Fig. 2, B–D
). In leukemic T-cells from 4 of 11 cases (36%), we found an abnormal diffuse, "patchy" nuclear staining with or without cytoplasmic staining (Table 2
; Fig. 2, E and F
).
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. Three major shifted bands, which correspond to protein-DNA complexes containing Ikaros, were detected, reminiscent of the results from Ik-BS1 EMSA on murine thymocytes. This triplet binding pattern was specific, because 60-fold excess of the unlabeled wild-type Ik-BS1 oligonucleotide, but not the mutant Ik-BSM oligonucleotide, was able to inhibit the mobility shift (Lanes 3 versus 4, respectively). In contrast, nuclear extracts from MOLT-3 cells or leukemic T-cells from T-ALL patients revealed no detectable mobility shifts of the Ik-BS1 probe (Fig. 2H)
.
Molecular Characterization of Ikaros Transcripts in T-Lineage ALL Cells.
RT-PCR and nucleotide sequencing were used to examine normal thymocytes and bone marrow cells as well as leukemic T-cells for the expression of PCR-amplifiable Ikaros transcripts (Fig. 3)
. A single 1.4-kb PCR product was observed in normal fetal thymocytes, and the PCR clones had the coding sequence of wild-type Ik 1 (Fig. 3B
; Table 2
). Similarly, a single 1.2-kb PCR amplification product was detected in normal bone marrow cells, and the PCR clones had the coding sequence of wild-type Ik-2 (Fig. 3B
; Table 2
). By comparison, the predominant PCR products in leukemic cells from children with T-ALL, with the exception of T-ALL# 14, were smaller than Ik-2 (Fig. 3B)
.
|
; Figs. 3C
and 4
). Six of 10 clones from MOLT-3 cells corresponded to an aberrant Ik-2 with a single amino acid substitution (G
V) plus a 20-amino acid insertion (TYGADDFRDFHAIIPKSFSR) due a 60-bp insertion immediately upstream of exon 4 at the exon 2/exon 4 junction and a 10-amino acid deletion ( KSSMPQKFLG) mutation with 30 bp missing at the 3' end of exon 6 (Table 2)
. Three of the remaining four clones had the wild-type Ik-8 sequence, and one was mutant Ik-8 with the same 30-bp deletion at the 3'-end of exon 6 as in Ik-2.
|
; Fig. 3C
). The inserted 20-amino acid peptide is likely encoded by a small exon, which we named exon 2a. A computer analysis of the exon 2a amino acid sequence indicated that exon 2a encodes a perfect -helix, which is followed by a flexible region. The flexible region (KSFSR) is located upstream from the DNA binding zinc fingers (F2 and F3 in Fig. 3, A and D
) and consists of two positively charged residues and two serine residues that have high binding affinity for the phosphate backbone of DNA. Moreover, our structure-based modeling studies (13
, 14)
indicated that the exon 2a-encoded peptide takes the position of the DNA-binding zinc finger F1, which is found in amino acid sequences of Ik-1, Ik-3, and Ik-5 but not in Ik-2 (Fig. 3, A and D)
. Therefore, the presence of exon 2a may significantly alter the Ikaros-specific, DNA-binding activity of Ik-2 because exon 2a-encoded peptide is likely incorporated into the DNA-binding region, as illustrated in Fig. 3D
. This notion is supported by the observed abnormal subcellular compartmentalization of Ikaros protein and lack of high-affinity Ikaros DNA-binding activity in leukemic T-cells expressing Ik-2 containing exon 2a.
Eight PCR clones from JK-E6–1 cells had the wild-type coding sequence of the dominant-negative Ikaros isoform Ik-4. Similar to JK-E6–1 cells, primary leukemic cells from 8 of 10 T-ALL patients that were analyzed expressed the dominant-negative Ikaros isoform Ik-4 (Table 2
; Fig. 4
); T-ALL #2 and #16 expressed only wild-type Ik-4. All nine PCR clones from T-ALL #3 had the abnormal Ik-4 (Ik-4, KSSMPQKFLG) coding sequence with the 30-bp deletion at the 3' end of exon 6, identical to the deletion found in MOLT-3 cell line. T-ALL #5 and #6 expressed wild-type Ik-4, along with wild-type or the KSSMPQKFLG deletion form of Ik-2. Six of 7 PCR clones from T-ALL #12 had the aberrant Ik-4 coding sequence with the deletion, and the remaining clone was an aberrant Ik-2 with the same deletion. Patient #18 expressed both wild-type and KSSMPQKFLG deletion forms of Ik-4, along with wild-type Ik-1 and Ik-2. Finally, leukemic cells from patient #4 expressed deletion forms of the dominant-negative Ikaros isoform Ik-7 (sequence of 7 of 10 PCR clones) and DNA-binding Ikaros isoform Ik-2 (sequence of 3 of 10 PCR clones). The observed NH2 -terminal insertions and COOH-terminal deletions did not cause frame shift and therefore did not change the downstream amino acid sequences.
Thus, extending the confocal microscopy, EMSAs, and Western blot analyses, RT-PCR and sequencing confirmed that each T-ALL case expresses dominant-negative and/or abnormal isoforms of Ikaros; T-ALL cell lines JK-E6–1 and MOLT-3 as well as leukemic cells from 9 of 10 patients with T-ALL expressed dominant-negative Ikaros isoforms, including Ik-4 (JK-E6–1 and 8 of 10 T-ALL patients), Ik-7 (1 of 10 patients), and Ik-8 (MOLT-3). Furthermore, in 6 of 10 T-ALL cases as well as in the MOLT-3 cell line, the PCR clones with coding sequences of Ik-2, Ik-4, Ik-7, and Ik-8 had a specific deletion at the 3' end of exon 6.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the present study, we sought to determine whether abnormal Ikaros expression and function could contribute to the development of childhood T-ALL. Our findings provide unprecedented evidence that, in contrast to normal thymocytes and bone marrow cells, which express the DNA-binding Ikaros isoforms Ik-1 and Ik-2, leukemic cells from children with T-ALL preferentially transcribe Ikaros mRNA species lacking two or more of the exons 3, 4, and 5 that encode crucial DNA-binding zinc finger domains. Consequently, these leukemic cells primarily express non-DNA-binding dominant-negative isoforms of Ikaros (Ik-4, Ik-7, and Ik-8), which display abnormal subcellular compartmentalization patterns. Nuclear extracts from leukemic T-cells failed to bind DNA in mobility shift assays using a DNA probe containing an Ikaros-specific DNA binding sequence, whereas nuclear extracts prepared from normal human thymocytes specifically bound this probe in monomeric or multimeric protein/DNA complexes. These results indicate that the posttranscriptional regulation of alternative splicing of Ikaros RNA is defective in leukemic cells from children with T-ALL. Furthermore, the absence of Ikaros-specific, DNA-binding activity in leukemic cells with an abnormal patchy-diffuse nuclear Ikaros staining pattern (e.g., T-ALL#3, #12, and #14) indicated altered DNA binding properties of Ikaros-containing complexes in some of the T-ALL patients.
A recurring deletion of a 10-amino acid peptide, which is located in close proximity to the conserved bipartite transcription activation domain (7) within the first 81 amino acids of exon 7 adjacent to the COOH-terminal zinc finger dimerization motifs, was detected in leukemic T-cells from 6 of 10 T-ALL patients as well as in the MOLT-3 cell line and involved Ik-2, Ik-4, Ik-7, and Ik-8 coding sequences. The structural changes caused by this deletion could affect the accessibility of the mutant Ikaros activation domain for interactions with members of the basal transcription machinery and stability of such interactions. These IKAROS deletion mutants could also be impaired in their ability to form dimers or other higher order complexes with other IKAROS isoforms or other proteins. Such impairments could lead to altered DNA binding or altered subcellular localization of IKAROS, as we observed in the experiments described above. These possibilities will be examined further in future experiments.
In MOLT-3 cells as well as primary leukemic cells from one of the children with T-ALL, a unique 21-amino acid insertion (VTYGADDFRDFHAIIPKSFSR) was found between the domains encoded by exon 2 and exon 4 of Ik-2. This peptide is likely encoded by a small exon, which we named exon 2a, that shows 90% homology to an exon described in a radiation-induced mouse thymoma cell line (5) . The cause for the preferential expression of exon 2a in leukemic T-cells is presently unknown but may represent an error that occurred during the programmed alternative splicing of Ikaros pre-mRNA. Computer modeling studies indicated that the exon 2a-encoded peptide is likely incorporated into the DNA-binding region and therefore may significantly alter the Ikaros-specific DNA-binding activity of Ik-2. This notion was supported by the observed abnormal subcellular compartmentalization of Ikaros protein and lack of high affinity Ikaros DNA-binding activity in leukemic T-cells expressing Ik-2 containing exon 2a.
Taken together, our findings provide direct evidence that children with T-ALL have mutations in Ikaros and express high levels of dysfunctional dominant-negative Ikaros isoforms. Our study extends previous studies in mice, which demonstrated that germ-line mutant mice expressing dominant-negative isoforms of Ikaros develop T-ALL, and implicates the Ikaros gene in the leukemogenesis of childhood T-ALL. Recent studies have shown that immature lymphocyte precursors express DNA-binding isoforms of Ikaros that localize to centromeric heterochromatin, which may lead to gene silencing (4 , 9 , 10) . Thus, Ikaros might play an important role in recruitment and centromere-associated silencing of growth-regulatory genes (4 , 9 , 10) . An abundance of dominant-negative or mutant Ikaros isoforms that no longer bind DNA would interfere with centromeric recruitment and repression of specific genes during lymphocyte development. Expression of Ikaros isoforms incapable of lineage-specific gene silencing might also contribute to the lineage infidelity observed frequently in T-ALL (3) . To our knowledge, this is the first report to document the expression of dominant-negative and mutant isoforms of Ikaros in childhood T-lineage ALL. Our report extends our recent study that implicated the Ikaros gene in the leukemogenesis of infant ALL (8) .
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FOOTNOTES |
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2 To whom requests for reprints should be addressed, at Hughes Institute, 2665 Long Lake Road, Suite 330, St. Paul, MN 55113. Phone: (612) 697-9228; Fax: (612) 697-1042.
3 The abbreviations used are: ALL, acute lymphoblastic leukemia; T-ALL, T-cell ALL; CCG, Children’s Cancer Group; RT-PCR, reverse transcription-PCR; EMSA, electrophoretic mobility shift assay.
Received 2/24/99; revised 5/13/99; accepted 5/13/99.
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